Dose selection study designs in early phase II clinical trials

Abstract

In the pharmaceutical industry, dose selection is a critical step in early phase II clinical trials. A nonparametric method of dose allocation, Binary Dose Spacing (BDS) is proposed. The BDS design is compared to another nonparametric method, Equal Dose Spacing (EDS) and to several parametric models—symmetric and non-symmetric. The methods of comparisons include A-, D- and D-optimality and the steepest slope—obtained using regression analysis on simulated data—between the zero dose and the lowest active dose and between pairs of active doses, for each design. The BDS, design outperforms the EDS design using D and E-optimality in a linear model when the number of doses is greater than or equal to three and r≤.75 ( r∈&parl0;0,1&sqbr0; give the EDS high dose). For A-optimality, it does better when the number of doses is greater than or equal to two and r≤.5 . For simulated data, the BDS performed as good as the EDS design. For the parametric models, solutions obtained based upon the D-optimality criterion are used to make model comparisons and to simulate data. Theses models are analyzed with and without a placebo group- Robustness to initial guesses of the model parameter(s) are investigated. When there only active doses, the efficiency of the D-optimal design to k-point equally spaced designs is computed. When there is a placebo in the model, the result that the D-optimal solution is supported at two or three points is not substantiated, except for the normal distribution. For simulated data, the BDS design performed best against the normal distribution, then the logistic distribution and finally the Richards models. It does as well or better at identifying the MinED in all cases and does better against symmetric models than against non-symmetric models. The BDS is advantageous over optimality criteria in that no underlying parametric model need be assumed and there can be several doses in the model without assumptions regarding the relationship between the doses. The other parametric models considered performed just as well as the logistic distribution in terms of the efficiency to departures from the D-optimal solutions. ^